The effects of RNA editing in cancer tissue at different stages in carcinogenesis

Abstract

RNA editing is one of the most prevalent and abundant forms of post-transcriptional RNA modification observed in normal physiological processes and often aberrant in diseases including cancer. RNA editing changes the sequences of mRNAs, making them different from the source DNA sequence. Edited mRNAs can produce editing-recoded protein isoforms that are functionally different from the corresponding genome-encoded protein isoforms. The major type of RNA editing in mammals occurs by enzymatic deamination of adenosine to inosine (A-to-I) within double-stranded RNAs (dsRNAs) or hairpins in pre-mRNA transcripts. Enzymes that catalyse these processes belong to the adenosine deaminase acting on RNA (ADAR) family. The vast majority of knowledge on the RNA editing landscape relevant to human disease has been acquired using in vitro cancer cell culture models. The limitation of such in vitro models, however, is that the physiological or disease relevance of results obtained is not necessarily obvious. In this review we focus on discussing in vivo occurring RNA editing events that have been identified in human cancer tissue using samples surgically resected or clinically retrieved from patients. We discuss how RNA editing events occurring in tumours in vivo can identify pathological signalling mechanisms relevant to human cancer physiology which is linked to the different stages of cancer progression including initiation, promotion, survival, proliferation, immune escape and metastasis.

Keywords: ADARs; RNA editing; RNA editing in cancer; cancer development.

Figure 1.

The scheme of A-to-I (A) and C-to-U (B) deamination. Deamination, catalysed by enzymes called deaminases, is the process of removing an amino group from a molecule, usually with the amino group being released as ammonia. (A) ADARs mediate the adenosine deamination process on C6 (amino group at C6 position is marked in red) which results in inosine formation. During translation inosine is recognized as guanosine and thus a different amino acid can be incorporated into the protein during its synthesis. (B) C-to-U deamination mediated by APOBECs is a very similar hydrolytic deamination reaction where cytosine is converted to uracil; this change can also recode protein open reading frames. The A-to-I and C-to-U deaminases are distantly evolutionarily related to each other and share similar zinc-containing active sites

Figure 2.

Scheme of ADAR1, 2 and 3 protein domains. All ADARs have an evolutionarily conserved catalytic deaminase domain at their C termini and dsRBD domains with nuclear localization signals (two dsRBDs in ADAR2 and ADAR3 and three in ADAR1 isoforms) closer to the N termini. There are two isoforms of ADAR1: ADAR1p150, which has two Z domains and nuclear export signal (NES); and ADAR1p110, which has one Z domain and lacks the NES. ADAR3 possesses an R domain. Amino acid lengths of ADARs are shown in brackets

Figure 3.

Schematic view of APOBEC proteins relevant to RNA editing in cancer. APOBEC1 and APOBEC3A each have one zinc-dependent catalytic domain (CD), while APOBEC3B and APOBEC3G have two. Amino acid lengths of APOBEC proteins are shown in brackets

Figure 4.

ADAR RNA editing in the three main cancer stages. Edited transcripts presented in relation to the cancer steps they affect. Transcripts for which the edited form is the one associated with cancer are marked in black, while transcripts for which the unedited form or reduced RNA editing level are associated with cancer are marked in red. The GLI1 transcript is marked in both red and black due to its opposite effects, depending on cancer type